3alpha, 4alpha and 5beta, 6beta-cyclopropano-pregnene derivatives



Unite rates 3,080,386 3ot,4-a AND 5,8,6/3-CYCLGPROPANO-PREGNENE DERIVATIVES Lawrence H. Knox, Mexico City, Mexico, assignor to Syntax S.A., Mexico City, Mexico, a corporation of Mexico No Drawing. Filed Apr. 13, 1962, Ser. No. 187,293 20 Claims. (Cl. 269-3971) The present invention relates to novel cyclopentanophenanthrene derivatives and to a process for the production thereof.

More particularly, the present invention relates to novel 3a,4ot (cyclopropano) A -pregnen-20-0ne, Semi-(cyclopropano)-A -pregnen-20-one derivatives, to the l7a-hydroxy, 16-methyl and 16tx-hydroxy derivatives thereof, to the corresponding 17w and/or Mot-hydrocarbon carboxylic acid esters and to the corresponding 16a,17a-cyc1ic acetals and ketals.

The novel compounds of the present invention are represented by the following formulas;

A15 t5 QU oi1-ooo1t= on -00011 In the above formulas X represents hydrogen, fluorine or chlorine; R may be hydrogen, hydroxyl or a hydrocarbon carboxylic acyloxy group of less than 12' carbon atoms; R indicates hydrogen, e-methyl, fi-rnethyl, Ot-hydroxyl or an (1-hydI'OOafbOl'l carboxylic aeyloxy group of less than 12' carbon atoms; R and R together represent the group attest" i if;

active progestational agents, possessing anti-ovulatory, anti-estrogenic, and anti-gonadotrophic properties.

The novel compounds of the present invention are prepared by the process illustrated by the following equation:

(I) (III) I l CH; CH:

(5:0 (5:0 a 7 R Jwv R1 1W R1 1 CHCOOR err-000R: (1v) In the above formulas R, R R and X have the same meaning as previously set forth.

The starting compound (I) of the process just outlined outlined is prepared from the corresponding A -pregnen-' Sfl-ol-ZO-one derivative by conventional tosylation in pyridine withtosyl chloride, followed by conventional dehydrotosylat ion of the obtained S-tosylate in collidine, at reflux temperature, for a period of time of the order ofl- /z hours. The starting compound (I) thus produced is selected from the group consisting of A -pregnadien-20- one and the l6-rnethyl, l6a-hydroxy, 16a-acyloxy, 17ahydroxy, 17u-acyloxy and 160:,170t-(di-10Wl alkyl) methylenedioxy derivatives thereof.

In accordance with the above equation, the startin compound (I) is treated with an alkali metal trichloroacetate, preferably sodium trichloroacetate, in a suitable solvent such as bis-(Z-methoxyethyl) ether at approxiog a 20i-one (II; X=Cl) and 1',1-dichlorocyclopropano-(2'3; fl,6;3)-A -pregnen-2O-one (III; X=Cl)' derivatives.

Upon treatment of the starting compound (I) with diazomethane in the presence of copper powder, followed by' chromatography of the resulting product, there are obtained the corresponding cyclopropano-(1',2';3'a,4a)-A preg'nen-ZO-one (II; X=H) and cyclopropano-(l', 2;5fi, 6B)-A -pregnen-20-one (III; X=H) derivatives.

Upon reaction of the starting compound (I) with an alkali metal monochlorodifluoroacetate, preferably sodium monochlo-rodifluoroacetate, in a suitable solvent such as diglyme, at reflux temperature, for a period of time of the order of 20 minutes, followed by chromatography of the resulting product, there are produced the corresponding 1,l' difluorocyclopropano (2',3';3u,4a)-A -pregnen-20- one (II; X=F) and 1,l'-difluorocyclopropano-(2',3';5B, 6B)-A -pregnen-20-one (III; X=F) derivatives.

The reaction of the starting compound (I) with a lower alkyl diazoacetate such as ethyl diazoacetate, in the presence of copper powder, in a suitable solvent, such as 1,2- dimethoxy-ethane, at reflux temperature and for a period of time of the order of 4 /2 hours, yields a product which upon chromatography is separated into the corresponding 1 oarbethoxycyclopropano (2',3';3a,4ot) A pregnen 20-one (IV; R =ethy1) and 1'-carbethoxycyclopropano- (2'3'53,65)-A -pregnen-20-one (V; R ==ethyl) derivatives.

mthe final compounds of the above described types where a 17ot-acyloxy group is present, the acyloxyis conventionally' hydrolyzed with a base, thus affording the corresponding l7or-free alcohols.

The l'-canbethoxycyclopropano derivatives (IV, V; R =ethyl) of the present invention, upon conventional saponification with a base, yield the corresponding 1-carboxycyclopropano derivatives (IV, V; R =H). This hydrolysis may be concommitant with the saponification of acyloxy groups, when they are present in the same molecule.

The final compounds of the present invention having a 16a,17a-(di-10We1 alkyl) methylenedioxy grouping are converted into the corresponding 16a,17a-di0ls by treatment with 60% formic acid, at steam bath temperature, for a period of time of the order of one hour..

The 17a-hydroxyl group of compounds of the present invention is conventionally acylat'ed, in the presence of p-toluenesulfonic acid, with a suitable acylating agent, such as an anhydride derived from a carboxylic acid of the hereinbefore defined type thus producing the corresponding 17nz-acyloxy derivatives.

The l6a-hydroxyl group of compounds of the present invention is secondary and therefore is conventionally acylated in pyridine with an acylating agent, as for example propionic anhydride or caproic anhydride, thus affording the corresponding 16m-acyloxy derivatives.

The following specific examples serve toillus'trate, but

are not intended to limit the scope of the present" invention:

PREPARATION 1 A: solution of s g; f pregnenolone in 25 cc. er -syn;

dine was cooled to 0 C. Under stirring there was added 1.3 g. of tosyl chloride, the mixture was kept for 16 hours} at 0 C., diluted with 100' cc. of chloroform, washed with dilute hydrochloric acid, water, aqueous sodium bi-'- fractions from acetone-hexane aflorded A -pregnadien- 20-one.

By the same procedures, f17a-acetoxy-pregnenolone, 16zx-1'I16thYI-Pl6gtl6n0l0rl6, 16/3 methyl-pregnenolone, 17a- -acetoxy-l6a-methyl-pregnenolone and l6a,l7ot-dihydroxypregnenolone-l6,17 acetonide were respectively converted into 17a-acetoxy-A -pregnadien-20'one, 16a-methyl-A pregnadien-ZO-one, l6/8-methyl-A -pregnadien 20 one, l7a-acetoxy-l6a-rnethyl-M -pregnadien-ZO-one and 16a, 17-isopropylidendioxy-A -pregnadienQO-one.

Example I To a solution of 2 g. of A -pregnadien-20-one in 50 cc. of diglyme [bis(2-methoxyethyl-)ether] at 125 C. there was added 4.4 g. of sodium trichloroacctate in 10' equal portions at 10 minute intervals. The reaction mixture was then cooled, the formed sodium chloride filtered off, andthe filtrate evaporated to dryness under reduced pressure. The residue was conventionally chromatog'raphed on Florisil, thus yielding two products, which upon crystallization from methanol furnished 1,I'-dichlorocyclopropano-(2',3";3ct,4u)-A -pregnen-2O-one and 1',

l'-dichlorocyclopropano- (2',3;5 8,6 3) n -preg'nerr-zo-orre.

Example II Example 111 A mixture of 2 g. of A -pregnadien-2O one, 20 cc. of l,2-dimethoxy ethane and 300 mg. of freshly prepared copper powder was heated to reflux temperature, then there was added dropwise with stirring, a solution of 3.4 g. of ethyl diazoacetate in 5 cc. of" 1,2 -dimethoxy ethane over a period of 2 hours. Refluxing was continued for an additional 2.5 hours. The catalyst was thereafter filtered off and the filtrate evaporated to dryness. The residue was conventionally chromatographed on Florisil, thus yielding two products which upon crystallization from acetone-hexane furnished l-carbethoxycyclopropano,-(2",3; 3a,4 z)-A pregnen-20-one and 1'-carbethoxycyclopropano-(2,3';5fl,6fl)-A -pregnen-20-one.

Example IV A mixture of 2" gjof A -pregnadien20-one, cc. of diglyme and 4 g. of sodium monochlorodifluoroacetate was refluxed for 10 minutes, then cooled to 50 C., an additional 4 g. of the same salt were thereafter added. and the resulting mixture again refluxed for 10 minutes. The reaction mixture was cooled, the formed sodium chloride filtered olf and the filtrate evaporated to dryness under reduced pressure. The residue was conventionally chromatographed on Florisil, thus yielding two products,- which upon crystallization from methanol furnished l',l'-difluorocyclopropano-(2',3';30:,411)-A pregnen 20- one and 1',1-difluorocyclopropano-(2',3';5fl,6,6)-A *preg nen-20-one.

Example V 16ot-methyl-A -pregnadien-2O-one was treated in accordance with Example I, thus yielding 1',1'-dichlorocyclopropano'-(2,3;3a,4)-16a-methyl A -pregnen-20 one and l,'1"dichlorocyclopropano-(2',3';5/3,6 3) l6a-methyl A -pre'gnen-ZO-one.

--1.,1'-difiuorocyclopropano-(2,3255,613)-17a acetoxy-A Example VI 16a-methyl-A -pregnadien-20-one was treated following the procedure described in Example II to produce cyclopropano (1',2';3 x,4a) l6a-methyl-A -pregnen-20- one and cyclopropano-(1,2;5fi,6,8)-16a-methyl-A -pregnen-ZO-one.

Example VII l6a-methyl-A -pregnadien-20-one was treated according to Example III, thus yielding l-carbethoxycyclopropano-(2',3';3a,4u)-16a-methyl-A -pregnen 20 one and l'-carbethoxycyclopropano-(2332513165)-l6a-methyl- A -pregnen-2O-one.

Example VIII 16emethyl-A -pregnadien-20-one was treated by the method of Example IV, to give 1',1'-difiuorocyclopropano- (2',3;3a,4a)-l6e-methyl-A -pregnen-20-one and 1',1'- difiuorocyclopropano-(2',3';5{3,6[3)-16a methy1-A -pregnen-ZO-one.

Example IX 16,8-methyl-A -pregnadien-20-one was treated in accordance with Example I, thus yielding 1,1-dichlorocyclopropano-(2',3';3a,4a)-16fi-methyl A pregnen-ZO- one and 1',1'-dichlorocyc1opropano-(2,3;5B,6B)46 8- methyl-A -pregnen-20-one.

Example X 16fi-methyl-A -pregnadien-20-one was treated following the procedure described in Example II, to produce cyc1\'. propano-(l,2';3|a,4a)-16/3-methyl-A pregnen 20- one and cyclopropano-(1',2;55,6p)-l6fi-methyl-A -pregnen-ZO-one.

Example XI 16fl-rnethyl-A -pregnadien-20-one was treated according to Example III, thus yielding 1'-carhethoxycyclopropano-(2,3;3a,4a) 16,8 methyl-M-pregnen-ZO-one and l-carbethoxycyclopropano-(2',3';5fi,6,8)-16B-methyl- A -pregnen-20-one.

Example XII 16B-methyl-A -pregnadien-ZO-one was treated by the method of Example IV, to give 1',1-difluorocyclopropano-(2,3';3a,4u) lfi-methyl-M-pregnen 20-one and 1,1'-difluorocyclopropano-(2,3;5/3,6,8)-16fi-1nethyl A pregnen-ZO-one.

Example XIII l7a-acetoxy-A pregnadien-20-one was treated in accordance with ExampleI, thus yielding 1,1'-dichl0rocyclopr-opano-(2',3;3a,4)-17e aceto-xy- A -pregnen- 20'one and 1',l'-dichlorocyclopropano-(2',3;5p,6fi)47aacetoxy-A -pregnen-ZO-one.

Example XIV 17a-acetoxy-A P-pregnadien-ZO-one .Was treated following the procedure described in Example II, to produce cyclopropano-(1,2;3a,4a)-17a-acetoxy A -pregnen-20- nen-ZO-one.

Example XV 17a-acetoxy-A -pregnadien-2O-one was treated according to Example III, thus yielding 1'-carbethoxycyclopropano-(2,3;3a,4a)-17e acetoxy-A pregnen 20-onc and 1-carbethoxycyclopropano-( 2',3 ;Sp,6/i)-17wacetoxy- A -pregnen-20-one. Example XVI '17a-acet0xy-A -pregnadien-2O-one was treated by the method of Example IV, to give 1',l'-difluorocyclopropano-(2',3';3a,4a) 17a acetoxy-A -pregnen-20-one and pregnen-ZO-one.

6 Example XVII 17e-acetoxy-l6a-methyl-A -pregnadien 20 one was treated in accordance with Example I, thus yielding 1,1- dichlorocyclopropano-(2',3';3a,4a)-17a acetoxy 16amethyl-Mpregnen-ZO-one and 1,1-dichl0rocyclopropano-(2',3';5,6,6/3)-l7a-acetoxy-16a-methyl-A pregnen- 20-one.

Example XVIII ,l7a-acetoxy-16a-methyl-A -pregnadien 20 one was treated following the procedure described in Example II to produce cyclopropano-(1',2';3a,4a)-17a-acetoxy-16umethyl-M-pregnemZO-one and cycl0propano-(l',2';5}3, 6B)-17a-acet0xy-16m-rnethy1-A -pregnen-20-one.

Example XIX 17a-acetoxy-16a-methyl-A -pregnadien 20 one was treated according to Example III, thus yielding 1'-carbethoxycyclopropano-(2,3;3a,4a) 17cc acetoxy-16amethyl-M-pregnen-ZO-one and 1-carbethoxycycl0propano-(2',3;513,6;8)-17a acetoxy-la methyl-M-pregnen- 20-one.

Example XX 17a-acetoxy-16a-methyl-A -pregnadien 20 one was treated by the method of Example IV, to give 1,1'-'difluorocyclopropano-(2,3';3a,4a) l7a-acetoxy-l6a-methyl-A -pregnen-20-one and 1',1' difluorocyclopropano- (2,3;5fi,6fi)-17a-acetoxy-16a-methy1-A -pregnen 20-one.

Example XXI Example XXIII :,17a-isopropylidendioxy-A pregnadien-20 one was treated according to Example III, thus yielding l-carlbethoxycyclopropano (2',3';3oz,4oc) 16m,17m-isopropy1- idendioxy-A -pregnen-20-one and 1-carbethoxycyclopropano (2',3;5,s,6 3) 160:,170: is opropylidendioxy A pregnen-ZO-one.

Example XXIV 16a,17a-isopropylidendioxy-A -pregnadienQ O-one was treated by the method of Example IV, to give 1',1'-difiuorocyclopropano (2',3'; 311,400 16a,17x isopropyli-dendioxy-M-pregnen-ZO-one and 1',1'-difiuorocyclopr0pano (2',3;5fl,6fi)4 6a,17a-i-sopropylidendioxy-A -pregnen- ZO-one. I Y

Example XXV A solution of 0.17 g. of potassium hydroxide in 0.2 cc of water and 2.5 cc. of methanol was added over 30 minutes to a boiling solution of 1 g. of 1,1' dichlorocycl'opropano (2',3';3ol,4u) 17cc acetoxy A pregnen QO-one in 30 cc. of methanol under an atmosphere-of ni-' trogen. Boiling was continued for a further 2 hours and the solution was then cooled, neutralized with acetic acid and concentrated under reduced pressure. Addition of water, followed by crystallization of the precipitated solid from acetone-hexane, produced 1',1-dich1orocyclopr0- pano-(2',3;3a,4u)-A -pregnen-17a-ol-2O-one.

The final compounds of Examples XIII, XIV, XVI, XVII, XVIII and XX were treated by the same procedure, thus affording theqcorresponding Hot-alcohols.

Example" XX VI:

1- g of 1,l -dichlorocyclopropano (-2,3 ';3a,4a)' 16a,!7a-isop-ropylidendioxy-A -pregnen-ZO-one was heated. on the. stream bath with 20 cc. of 60% formic acid. for 1 hour, cooled, diluted with water and the precipitate was. collected, washed with water, dried, and recrystallized from acetone-hexane, thus affording 1',1-dichlorocyclopropano-(2,3;3a,4a)-A -pregnene-l6a,l7u-diol-2O-one.

Using exactly the same conditions,

Example XX VII A mixture of 1 g. of l,1' dichlorocyclopropano- (2',3;3u,4u)-A -pregnene-l6a,l7u-diol-20-one, 4 cc. ofv pyridine and 2 cc. of propionic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave the 16-pr0pionew of I',1 -dichlorocyclopropano-(2,3';3e,4o)-A -preg- Irene-16a,l7a-diol-20-one.

The following starting compounds were treated by the same procedure:

1', 1-difluorocyclopropano-(2',3" ;5 18,618) -A -pregnene- 16a,17adiol-20-one,

1 "-carbethoxycyclopropano- (2',3' 55,65) -A -pregnene- 1601,17bz-(liOl-20-0116,

1 '-carbethoxy cyclopropano- (2',3 ';3 a,4a) -A -pregne'ne- 16,l7 adiol-20-one and cyclopr6pano-( 1 ,2 ;3 ot,4a) -A -pregnene-16a,17d-diol-2O- one,

thus yielding the respective 16-propionates.

Example XXVIII 8 1,1'-difluorocycloproparm-(2',3 255,65) -A -pregnen- 17oc-O1-2'O-OI16, 1,1-difiuorocyclopropano, cyclopropano(l',2';5/3;6B)-

A -pregnen-17a-ol-20-one and cyclopropano-( l,2;3a,4a) -A -pregnen-l7a-ol-20-one were treated by the same method thus yielding the corresponding 17-caproates.

Example XXIX l'-carbethoxycyclopropano-(2',3 ';3 01,40) -l7a-acetoxy-A pregnen-ZO-one,

1'-carbethoxycyclopropano-( 2',3 2518,65 -17m-acetoxy-'A pregnen-ZO-one,

1-carbethoxycyclopropano=(2',3 255,65) -l 7a-ace'to'xy- 16u-methyl-A -pregnen-ZO-one and l carbethoxycyclopropano- 2',3 ;3a,4a,)-17a-acetoxy- 16 a-methyl-A -pregnen-20-one were treated in accordance with Example XXV thus fornishing respectively 1'-carboxycyclopropane-( 2',3 ';3 a,4a) -A -pregnen- 17ccol-2-0-one,

|1'-carboxycyc1opropane- (2",3 ';5 5,6 8) -A -pregnen-1 7w ol-20-one,

l-carboxycyclopropane-(2',3';3u,4a) -'1=6e-methy1-A pregnen-17a-ol-20-one.

Example XXX The final products of Example XXIX were treated in accordance with Example XXVIII, thus giving the corresponding l7-caproates.

Example XXXI The 16-propionate of 1,l'-dichlorocyclopropano- (2',3';3a,4a)-A -pregnene:,17a-dio1-20-0ne and the '16 propionate 1',1'-difiuorocyclopropano-(2',3;5fl,6fl)- A -pregnene-16e,l7a-diol-20-one were treated in accordance with Example XXVIII giving respectively: the 16-propionate-l7-caproate of l,l-dichlorocyclopropano- (2',3';3m,4a)-A -pregnene-l-6a,17a-diol-2O-one and the 16-propionate- 17-caproate of l',1-difiuorocyclopropanov(2,3;5[3,6/3)-A -pregnene-l6m,17 c diol2()-one.

I claim:

1. A compound of the following formula:

wherein X is selected from the group consisting of hydrogen, fluorine and chlorine; R is a member of the group consisting of hydrogen, hydroxyl and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, e-methyl, fl-methyl, u-hydroxyl and an Ot-hYdI'OCQl'bOfi carboxylic acyloxy group of less than 12 carbon atoms; and R and R together represent the group wherein R is a lower alkyl group. 02. 1',l -dichlorocyc1opropano-( 2',3 ';3 05411) -A -pregnen- 2 -one.

9 3 1',1'-difluorocyclopropano-(2',3;3a,4u)-A -pregnen- ZO-one.

4. Cyclopropano-(1,2';3a,4u)-A -pregnen-20-one. 5 1', l -difluorocyclopropano-(2,3 ',3a,4ec) -16 tx-methyl- A -pregnen-20-one. 5

6. A compound of the following formula:

U X-C l wherein X is selected from the group consisting of hydrogen, fluorine and chlorine; R is a member of the group consisting of hydrogen, hydroxyl and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, a-methyl, fl-methyl, a-hydroxyl and an u-hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; and R and R together represent the group wherein R is a lower alkyl group.

7. 1,-1'-dichlorocyclopropano-(2',32513,65)-A -pregnen- ZO-one.

9. Cyclopropano-( 1',2';5;3,6;3) -A -pregnen-20-one.

10. '1',1'-difluorocyclopropano-(2',3;5B,6B) -.1 Got-methyl- A -pregnen-20-one.

11. A compound of the following formula:

oi r-ooom wherein R is a member of the group consisting of hydrogen, hydroxyl and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, oc-methyl, fi-methyl,

a-hydroxyl and an w-hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; R and R together represent the group if; WU q UHF-00 OR wherem R is a member of the group consisting of hydrogen, hydroxyl and a hydrocarbon carb-oxylic 'acyloxy group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, tat-methyl, B-rnethyl, whydroxyl and on a-hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; R and R together represent the group wherein R is a lower alkyl group; and R is a member of the group consisting of hydrogen and lower alkyl.

17. 1' earhethoxycyclopropano (2',3';5,B,6,B) A pregnen-ZO-one.

I18. 1 carboxycyclopropano (2,3;5;3,6 9)-A -pregnen-ZO-one.

19. 1 carbethoxycyclopropano (2',3';5fi,6,9) 16ccmethyl-M-pregnen-ZO-one.

20. 1' carbethoxycyclopropano (2',3;5fl,6fi) 16 6- methYl-A -pregnen-ZO-one.

No references cited. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 